A protein found in the spinal fluid of cognitively healthy adults predicted the onset of mild cognitive impairment and dementia years before symptoms appeared, a new study has found. The findings could lead to new targets for treating or preventing Alzheimer’s and other dementias.
Combined with last week’s news of a previously unknown path of cell death in Alzheimer’s disease and vascular dementia, these predictive biomarker results highlight how fast new avenues in Alzheimer’s research are opening up.
The researchers discovered that a low level of the synaptic protein NPTX2 in cerebrospinal fluid is a potential independent risk factor for mild cognitive impairment and Alzheimer’s disease. It also improves cognitive impairment prediction despite controlling for levels of traditional biomarkers and well-established genetic risk factors for Alzheimer’s.
More than 250 predominantly middle-aged white adults participated in the study. It was concluded that the findings were consistent with and expanded upon previous research by establishing that measurements of NPTX2 in cerebrospinal fluid could predict the onset of MCI within or even beyond seven years prior to the onset of symptoms.
Earlier Predictors Sought
Mild cognitive impairment (MCI), characterized by moderate memory loss or difficulties with other cognitive processes such as language or executive function, affects up to 18% of 60-year-olds and older, according to the Alzheimer’s Association. People with MCI are able to perform the majority of normal daily activities, but they have a higher risk of developing Alzheimer’s disease or another form of dementia.
It is estimated that 6.7 million Americans age 65 and older are living with Alzheimer’s dementia, with that number expected to double by 2050. The increasing prevalence of dementias has accelerated the search for improved and earlier predictors and treatment targets that prevent or delay progression.
Currently, there is only one FDA-approved drug on the market – Leqembi – that can even modestly slow the symptoms of Alzheimer’s in its early stages, and there are no cures or preventive measures.
“Our research shows declining levels of NPTX2 occur many years prior to the emergence of MCI or Alzheimer’s symptoms, which raises the possibility of developing new therapeutics that target NPTX2,”
said corresponding author Anja Soldan, associate professor of neurology at the Johns Hopkins University School of Medicine.
In addition, it appears that this protein is not unique to Alzheimer’s disease, and these findings may apply to a number of other neurodegenerative disorders. So if scientists can discover ways to increase NPTX2 levels, it could be used to detect and potentially treat other forms of memory loss or cognitive impairment.
Measuring NPTX2 Levels
Researchers conducted baseline medical and cognitive exams on 269 cognitively normal individuals for the study, which included adults recruited by the National Institutes of Health and Johns Hopkins Medicine, and collected spinal fluid samples biannually.
The average age of participants at the start of the study was 57.7. Almost all were white, 59% were female, the majority had a college degree, and 75% had a close relative with Alzheimer’s.
In addition to measuring NPTX2 levels, the principal anomalous proteins found in Alzheimer’s patients, beta-amyloid, total tau, and phosphor-tau, were also measured. For an average of 16 years, subjects were evaluated clinically and cognitively.
The results revealed that 77 subjects developed MCI or dementia within or after seven years of their baseline measurements. 88% of these participants had Alzheimer’s as the primary or secondary cause of dementia.
The findings also revealed that those who progressed to mild cognitive impairment had about 15% lower levels of NPTX2 at baseline compared to those who remained unimpaired, a significant difference even after accounting for baseline Alzheimer’s biomarker levels and genetic factors.
Routine Testing Still a Long Way Away
Furthermore, higher baseline tau and phosphor-tau levels were associated with greater decreases in NPTX2 over time, implying that NPTX2 may decline in response to tau pathology.
“Currently, we only have drugs that modify mild symptoms of Alzheimer’s disease and nothing right now to give people who are cognitively normal but at higher risk,”
Soldan said. But, if and when that changes, Soldan said, accurately predicting such risk will be critical in targeting treatments.
Soldan also cautioned that a simple method for routinely testing spinal fluid samples for NPTX2 levels is “a long way off,” and that additional research is required to ascertain what factors affect the protein’s levels. It is possible that genetics, lifestyle factors, or a combination of both are potential underlying causes.
Soldan also emphasized the new study’s limitations, such as the study population’s racial and educational composition.
Reference:
- Soldan, A., Oh, S., Ryu, T., Pettigrew, C., Zhu, Y., Moghekar, A., Xiao, M.-F., Pontone, G.M., Albert, M., Na, C.-H. and Worley, P. (2023). NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment. Ann Neurol DOI: 10.1002/ana.26725